27
MulticoMponent reactions for the synthesis of pyrroles Under The Supervision Of : Dr. Shafiullah Presented By: Shaheen Siddiqui Roll No:2012 OCHM15 EN.NO:GD9318

multicomponent raction

Embed Size (px)

Citation preview

MulticoMponent reactions for the synthesis of pyrroles

Under The Supervision Of:Dr. Shafiullah

Presented By: Shaheen Siddiqui Roll No:2012 OCHM15 EN.NO:GD9318

• Introduction• Multicomponent reactions : Definition And Importance• Importance of Pyrrole-Examples• Advantage of Multicomponent Reactions over other

Reactions• Synthesis of Pyrrole by different methods

• Application• Conclusion• References

•Present-day requirements for new synthetic methods go far beyond the traditional ones and can be summarized as follows:1. Use of simple and readily available starting materials.2. Experimental simplicity.3. Possibility of automation.4. Favourable economic factors, including the cost of rawmaterials, human resources and energy.5. Low environmental impact: use of environmentallyfriendly solvents, atom economyFor this reason, the creation of molecular diversity and complexity from simple and readily available substrates is one of the major current challenges of organic synthesis, and hence the development of processes that allow the creation of several bonds in a single operation has become one of its more attractive goals

•Multicomponent reactions (MCRs) are convergent chemical processes where three or more reagents are combined in such a way that the final product retains significant portions of all starting materials•They lead to the connection of three or more starting materials in a single synthetic operation with high atom economy and bond-forming efficiency, thereby increasing molecular diversity and complexity in a fast and often experimentally simple fashion

Umar, 03/22/2014

•Most important simple heterocyclic compound, found in a broad range of natural products, drug molecules and also of growing relevance in materials science•Present as a structural fragment of heme and chlorophyll, two pigments essential for life•Present in a large number of bioactive compounds including HIV fusion inhibitors and antitubercular compounds•Glucose sensors based on polypyrrole-latex materials and polypyrrole materials for the detection and discrimination of volatile organic compounds

•Based on the reaction between a β-enaminone and a α-haloketone•Original Hantzsch method was restricted to the use of

ethyl β-aminocrotonate.•Later on extented to include R2 substituents other than methyl and also the case of R5 = H•Yields for these reactions were normally below 50%

• Phenacyl bromide, acetylacetone and a variety of amines and β-cyclodextrin were heated in water at 60–70 C, the ⁰corresponding 1,5-diarylpyrroles were obtained in good to excellent yields(77% average)

•The reaction involved generating the supramolecular inclusion complex between β-cyclodextrin and phenacyl bromide in water at 50 C, followed by addition of the other reagents and stirring at ᵒ60–70 Cᵒ• The role of cyclodextrin was assumed to be the activation of phenacyl bromide through hydrogen bonding interactions of its bromine atom with hydroxy substituents in the cyclodextrin rim

•Three component reaction among β-dicarbonyl compounds, arylglyoxals and ammonium acetate in water, which affords 4-hydroxy-5-arylpyrroles in variable yields•β-ketoesters were employed as the dicarbonyl component

•β- ketoester undergoes keto-enol tautomerisation followed by aldol addition to arylglyoxals giving 1,4-dicarbonyl intermediate 1•It is then followed by a Paal–Knorr-type cyclization and double dehydration to yield the desired product

•Four-component reaction between acetylenedicarboxylates, succinimide or maleimide and two molecules of an isonitrile in refluxing dichloromethane.•Pyrroles are obtained in good to excellent yields•Average yield is 78%

•In pathway b, an initial addition of the isonitrile to the electron-defficient alkyne takes place to give species 13• Reaction of 13 with second molecule of isonitrile affords bis-ketenimine 14•Its reaction with the imide component followed by cyclisation gives the desired product,pyrrole•Use of sterically hindered isonitriles (e.g. tert-butyl isonitrile) prevented the generation of 14 because of steric hindrance •Intermediate 13 deprotonates the imide to give intermediate 15, and this is followed by a Michael addition that leads to product 16

•Three-component reaction between primary amines, alkyl acetoacetates and fumaryl chloride•Pyrrole derivatives thus obtained contain a 5-chloro substituent, together with carboxylic ester and carboxymethyl functional groups•Reaction occur at room temperature • Average yield is 78%

• Formation of β-enaminone 2, followed by its Michael addition onto a molecule of fumaryl chloride to afford 3•Intramolecular attack of the enamine nitrogen onto the acyl chloride function leading to the generation of the five-membered ring

•Loss of H2O and HCl give the desired product

•Four-component coupling of aldehydes, amines and nitroalkanes in the presence of a catalytic amount of samarium trichloride at 60 C ⁰which affords tetrasubstituted pyrroles •Moderate yield is obtained

•Initial formation of the imine 28 from the starting amine and one molecule of aldehyde•Samarium-catalyzed aldol-type self-condensation of 28 affords the α,β-unsaturated imine 29, which is attacked by the nitroalkane in a conjugate fashion to yield intermediate 30•An intramolecular proton transfer followed by cyclization affords a new intermediate 31, which then evolves to the final aromatic pyrrole following loss of water and HNO

•Entry to munchnones via an acylamino chromium carbene complex followed by a 1,3-dipolar cycloaddition with acetylenedicarboxylates that yields pyrroles•Average yield is 48%

•Acylation of the starting aminocarbene chromium complex

with benzoyl chloride to give an acylaminocarbene complex 54•Insertion of carbon monoxide to give a ketene complex 55•Ketene cyclizes to a metal-free Munchnone 56,that could be isolated if desired, with the demetalation facilitated by the presence of CO•1,3-dipolar cycloaddition to the alkyne followed by loss of a molecule of carbon dioxide, yields the final pyrrole

•Multicomponent reactions are particularly well suited for diversity oriented synthesis•Very powerful for synthesis aimed at carrying out structure–activity relationship (SAR) studies of drug-like compounds, which are an essential part of the research performed in pharmaceutical and agrochemical companies•For all these reasons, the development of new multicomponent reactions is rapidly becoming one of the frontiers of organic synthesis•Recent years have witnessed a steady growth in the development of MCRs that lead directly to heterocycles, the most important single class of compounds in the development of bioactive substances

•Pyrrole derivatives have great relevance in many fields of chemistry, and we have shown that Multicomponent Reactions are an excellent, multipurpose approach to Pyrrole synthesis•Besides the development of new reactions or improved conditions for the classical ones, future developments in this field will probably involve the application of multicomponent-based strategies to target-oriented synthesis•Very useful area of organic synthesis

• Multicomponent Reactions, ed. J. Zhu and H. Bienayme´ , Wiley-VCH, 2005• For a symposium in print on MCRs, see: Tetrahedron Symposia-in- Print, ed. I. Marek, 2005, vol. 67, p. 11299• F. Palacios, D. Aparicio, J. M. de los Santos and J. Vicario, Tetrahedron, 2001, 57, 1961• C. Cao, Y. Shi and A. L. Odom, J. Am. Chem. Soc., 2003, 125, 2880•D. J. St Cyr and B. A. Arndtsen, J. Am. Chem. Soc., 2007, 129, 12366• D. J. St Cyr and B. A. Arndtsen, J. Am. Chem. Soc., 2007, 129,12366